SUMMARY Peripheral arterial disease (PAD) is a major complication of systemic atherosclerosis. PAD afflicts over 8 million patients in the US and millions more around the world. Patients with PAD have problems from reduced blood flow to the leg resulting from the arterial occlusions and they suffer high rates of stroke and heart attack. There is a large unmet need for medical treatments to improve perfusion to treat PAD; currently, no medical treatment effectively increases blood flow to the leg in PAD. Numerous clinical trials attempting to increase angiogenesis have failed to provide long-lasting clinical improvements in PAD. In addition, the reason for the high rates of heart attack, stroke, and death associated with PAD are only incompletely understood. To meet this need for medical therapies to improve blood flow in PAD, we need a better understanding of what controls angiogenesis in PAD. Our approach is to integrate detailed mechanistic multiscale computational models with PAD-specific experimental data to simulate the pathophysiology and treatment of PAD. This project is based on the proposition that therapeutic approaches in PAD will be realized by growing blood vessels that are: stable, not leaky or malformed; and do not promote adverse inflammation. Therefore, we hypothesize that a major focus of therapeutic strategies in PAD must be on promoting the growth of normal blood vessels, including modulating immune cells for optimal angiogenesis. To advance the computational framework for therapeutic angiogenesis, we will build an integrative signaling network that includes VEGFA and its endothelial receptors VEGFR1, VEGFR2, and VEGFR3, co-receptors, and an associated pathway, Angiopoietin (Ang)-Tie, that plays an important role in vascular leakage and vascular stability. Inflammation is a hallmark of PAD and other ischemic diseases, and we will formulate experiment-based computational models of macrophage polarization, and design and test strategies that can shift the system toward a pro-angiogenic, pro-stability, non-leaky, and anti-inflammatory phenotype. This project will result in predictive, experimentally-validated models of important signaling pathways, with specific relevance to PAD. It will advance state of the art in modeling integrative interdependent signaling pathways at the cellular and tissue levels. The project will lead to a better fundamental understanding of PAD and its determinants and to translational applications.